Exaggerated coronary vasoreactivity to endothelin-1 in aged rats

Role of protein kinase C

Donna Hope Korzick, Judy M. Muller-Delp, Patrick Dougherty, Christine L. Heaps, Douglas K. Bowles, Kevin K. Krick

Research output: Contribution to journalReview article

19 Citations (Scopus)

Abstract

Objective: The interaction between advanced age and increased susceptibility to ischemic insult is well documented. Age-related increases in coronary vascular resistance, in part due to impaired dilator responses, have been reported. Our aim was to determine the role of endothelin-1 (ET-1) on enhanced constrictor responses in aged coronary arteries (CAs) and whether protein kinase C (PKC) signaling mechanisms impact ET-1 responses. Methods: Vasoreactivity was assessed in CAs isolated from aged (24 months; n=16) and adult (4 months; n=21) male F344 rats following ET-1 (10-10-10 -8) with and without specific ETA/ETB receptor antagonists (BQ-123, 1 μM; BQ-788, 30 nM) or the PKC inhibitor bisindolylmaleimide (Bis; 10-6 M). Constrictor responses to KCl (80 mM) were also measured and voltage-gated Ca2+ channel (VGCC) determined in isolated coronary smooth muscle cells. Dilator responses to acetylcholine (ACH) and sodium nitroprusside (SNP) were assessed. Results: Passive diameter was greater (357±19 vs. 309±9; p<0.02) while spontaneous tone was similar in 24 months vs. 4 months. ET-1 resulted in greater constriction in 24 months vs. 4 months (79% vs. 67%; p<0.01). Group differences persisted following selective ETB inhibition with BQ-788 (p<0.02), while BQ-123 abolished contractile responses to ET-1. Importantly, inhibition of ET-1 constriction by Bis occurred in 24 months but not 4 months (p<0.01). Constrictor responses to KCl and peak VGCC current density were similar in 24 months vs. 4 months (48% vs. 50%). No age-related differences were observed in ACH- or SNP-mediated dilation. Western blotting revealed increases in Ca2+-sensitive PKCα, -βI, and -βII levels with age, while eNOS and ETA receptor protein levels were unchanged. Conclusion: Aberrant ETA constrictor responses and directional changes in PKC are likely to contribute to coronary vascular pathology with advanced age.

Original languageEnglish (US)
Pages (from-to)384-392
Number of pages9
JournalCardiovascular Research
Volume66
Issue number2
DOIs
StatePublished - May 1 2005

Fingerprint

Endothelin-1
Protein Kinase C
Nitroprusside
Constriction
Acetylcholine
Coronary Vessels
Protein C Inhibitor
Inbred F344 Rats
Protein Kinase Inhibitors
Vascular Resistance
Smooth Muscle Myocytes
Blood Vessels
Dilatation
Western Blotting
Pathology
Proteins

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Korzick, Donna Hope ; Muller-Delp, Judy M. ; Dougherty, Patrick ; Heaps, Christine L. ; Bowles, Douglas K. ; Krick, Kevin K. / Exaggerated coronary vasoreactivity to endothelin-1 in aged rats : Role of protein kinase C. In: Cardiovascular Research. 2005 ; Vol. 66, No. 2. pp. 384-392.
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abstract = "Objective: The interaction between advanced age and increased susceptibility to ischemic insult is well documented. Age-related increases in coronary vascular resistance, in part due to impaired dilator responses, have been reported. Our aim was to determine the role of endothelin-1 (ET-1) on enhanced constrictor responses in aged coronary arteries (CAs) and whether protein kinase C (PKC) signaling mechanisms impact ET-1 responses. Methods: Vasoreactivity was assessed in CAs isolated from aged (24 months; n=16) and adult (4 months; n=21) male F344 rats following ET-1 (10-10-10 -8) with and without specific ETA/ETB receptor antagonists (BQ-123, 1 μM; BQ-788, 30 nM) or the PKC inhibitor bisindolylmaleimide (Bis; 10-6 M). Constrictor responses to KCl (80 mM) were also measured and voltage-gated Ca2+ channel (VGCC) determined in isolated coronary smooth muscle cells. Dilator responses to acetylcholine (ACH) and sodium nitroprusside (SNP) were assessed. Results: Passive diameter was greater (357±19 vs. 309±9; p<0.02) while spontaneous tone was similar in 24 months vs. 4 months. ET-1 resulted in greater constriction in 24 months vs. 4 months (79{\%} vs. 67{\%}; p<0.01). Group differences persisted following selective ETB inhibition with BQ-788 (p<0.02), while BQ-123 abolished contractile responses to ET-1. Importantly, inhibition of ET-1 constriction by Bis occurred in 24 months but not 4 months (p<0.01). Constrictor responses to KCl and peak VGCC current density were similar in 24 months vs. 4 months (48{\%} vs. 50{\%}). No age-related differences were observed in ACH- or SNP-mediated dilation. Western blotting revealed increases in Ca2+-sensitive PKCα, -βI, and -βII levels with age, while eNOS and ETA receptor protein levels were unchanged. Conclusion: Aberrant ETA constrictor responses and directional changes in PKC are likely to contribute to coronary vascular pathology with advanced age.",
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Exaggerated coronary vasoreactivity to endothelin-1 in aged rats : Role of protein kinase C. / Korzick, Donna Hope; Muller-Delp, Judy M.; Dougherty, Patrick; Heaps, Christine L.; Bowles, Douglas K.; Krick, Kevin K.

In: Cardiovascular Research, Vol. 66, No. 2, 01.05.2005, p. 384-392.

Research output: Contribution to journalReview article

TY - JOUR

T1 - Exaggerated coronary vasoreactivity to endothelin-1 in aged rats

T2 - Role of protein kinase C

AU - Korzick, Donna Hope

AU - Muller-Delp, Judy M.

AU - Dougherty, Patrick

AU - Heaps, Christine L.

AU - Bowles, Douglas K.

AU - Krick, Kevin K.

PY - 2005/5/1

Y1 - 2005/5/1

N2 - Objective: The interaction between advanced age and increased susceptibility to ischemic insult is well documented. Age-related increases in coronary vascular resistance, in part due to impaired dilator responses, have been reported. Our aim was to determine the role of endothelin-1 (ET-1) on enhanced constrictor responses in aged coronary arteries (CAs) and whether protein kinase C (PKC) signaling mechanisms impact ET-1 responses. Methods: Vasoreactivity was assessed in CAs isolated from aged (24 months; n=16) and adult (4 months; n=21) male F344 rats following ET-1 (10-10-10 -8) with and without specific ETA/ETB receptor antagonists (BQ-123, 1 μM; BQ-788, 30 nM) or the PKC inhibitor bisindolylmaleimide (Bis; 10-6 M). Constrictor responses to KCl (80 mM) were also measured and voltage-gated Ca2+ channel (VGCC) determined in isolated coronary smooth muscle cells. Dilator responses to acetylcholine (ACH) and sodium nitroprusside (SNP) were assessed. Results: Passive diameter was greater (357±19 vs. 309±9; p<0.02) while spontaneous tone was similar in 24 months vs. 4 months. ET-1 resulted in greater constriction in 24 months vs. 4 months (79% vs. 67%; p<0.01). Group differences persisted following selective ETB inhibition with BQ-788 (p<0.02), while BQ-123 abolished contractile responses to ET-1. Importantly, inhibition of ET-1 constriction by Bis occurred in 24 months but not 4 months (p<0.01). Constrictor responses to KCl and peak VGCC current density were similar in 24 months vs. 4 months (48% vs. 50%). No age-related differences were observed in ACH- or SNP-mediated dilation. Western blotting revealed increases in Ca2+-sensitive PKCα, -βI, and -βII levels with age, while eNOS and ETA receptor protein levels were unchanged. Conclusion: Aberrant ETA constrictor responses and directional changes in PKC are likely to contribute to coronary vascular pathology with advanced age.

AB - Objective: The interaction between advanced age and increased susceptibility to ischemic insult is well documented. Age-related increases in coronary vascular resistance, in part due to impaired dilator responses, have been reported. Our aim was to determine the role of endothelin-1 (ET-1) on enhanced constrictor responses in aged coronary arteries (CAs) and whether protein kinase C (PKC) signaling mechanisms impact ET-1 responses. Methods: Vasoreactivity was assessed in CAs isolated from aged (24 months; n=16) and adult (4 months; n=21) male F344 rats following ET-1 (10-10-10 -8) with and without specific ETA/ETB receptor antagonists (BQ-123, 1 μM; BQ-788, 30 nM) or the PKC inhibitor bisindolylmaleimide (Bis; 10-6 M). Constrictor responses to KCl (80 mM) were also measured and voltage-gated Ca2+ channel (VGCC) determined in isolated coronary smooth muscle cells. Dilator responses to acetylcholine (ACH) and sodium nitroprusside (SNP) were assessed. Results: Passive diameter was greater (357±19 vs. 309±9; p<0.02) while spontaneous tone was similar in 24 months vs. 4 months. ET-1 resulted in greater constriction in 24 months vs. 4 months (79% vs. 67%; p<0.01). Group differences persisted following selective ETB inhibition with BQ-788 (p<0.02), while BQ-123 abolished contractile responses to ET-1. Importantly, inhibition of ET-1 constriction by Bis occurred in 24 months but not 4 months (p<0.01). Constrictor responses to KCl and peak VGCC current density were similar in 24 months vs. 4 months (48% vs. 50%). No age-related differences were observed in ACH- or SNP-mediated dilation. Western blotting revealed increases in Ca2+-sensitive PKCα, -βI, and -βII levels with age, while eNOS and ETA receptor protein levels were unchanged. Conclusion: Aberrant ETA constrictor responses and directional changes in PKC are likely to contribute to coronary vascular pathology with advanced age.

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